Chronic progressive demyelination induces a microglial state with lysosomal dysfunction
Dysfunctional immune responses impair remyelination and contribute to neurodegeneration. While immune and metabolic responses to acute myelin injury are well characterized, myeloid cell adaptations to chronic myelin damage remain poorly understood. Here we performed a comparative analysis of genetic and toxic mouse models of acute and chronic demyelination, which identified a distinct microglial state associated with chronic demyelination, characterized by sustained pro-inflammatory activation, lysosomal lipid sequestration and reduced lipid droplet formation. Transcriptomics profiling further revealed a metabolic program marked by upregulated cholesterol synthesis and diminished sterol efflux. Treatment with a desmosterol mimetic possessing 24-dehydrocholesterol reductase inhibitor activity reversed this microglial state, attenuated pro-inflammatory signaling (including C-C Motif Chemokine Ligand 4 expression), reduced myelin damage and improved motor performance in a mouse model of leukodystrophy. Our findings uncover a pro-inflammatory microglial state characterized by lysosomal dysfunction and increased myelin reactivity, highlighting a novel therapeutic target for chronic demyelinating disorders.
Authors
- Alkmini Damkou (ORCID: https://orcid.org/0000-0002-5082-0790)
- Arthur Liesz (ORCID: https://orcid.org/0000-0002-9069-2594)
- Simon Besson‐Girard (ORCID: https://orcid.org/0000-0003-1194-5256)
- Simona Vitale
- Janos Groh (ORCID: https://orcid.org/0000-0002-7628-0163)
- Stefan Roth (ORCID: https://orcid.org/0000-0001-6823-2981)
- Martin A. Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Christoph Müller (ORCID: https://orcid.org/0000-0002-1163-2527)
- Marvin Reich (ORCID: https://orcid.org/0000-0002-4567-0994)
- Lennart Schlaphoff (ORCID: https://orcid.org/0000-0001-8043-4025)
- Klaus‐Armin Nave (ORCID: https://orcid.org/0000-0001-8724-9666)
- Sabina Tahirović (ORCID: https://orcid.org/0000-0003-4403-9559)
- Lena Spieth (ORCID: https://orcid.org/0000-0002-0308-0144)
- Georg Kislinger (ORCID: https://orcid.org/0000-0002-6559-7421)
- Anna Williams (ORCID: https://orcid.org/0000-0002-6329-382X)
- Martina Schifferer (ORCID: https://orcid.org/0000-0002-0500-8218)
- Stefan A. Berghoff (ORCID: https://orcid.org/0000-0002-3794-7295)
- Leon Hosang
- Gesine Saher (ORCID: https://orcid.org/0000-0003-3507-9604)
- Katrin Perez Anderson
- Astrid Feiten (ORCID: https://orcid.org/0000-0002-9134-2852)
- Mikael Simons (ORCID: https://orcid.org/0000-0001-5329-192X)
- Martin Zirngibl (ORCID: https://orcid.org/0000-0003-4485-8423)
- Lina Dinkel (ORCID: https://orcid.org/0000-0002-5380-3152)
- Özgün Gökçe (ORCID: https://orcid.org/0000-0001-6319-404X)
- Ludwig Huber (ORCID: https://orcid.org/0009-0004-6007-480X)
- Yakum Bertrand Nkeh (ORCID: https://orcid.org/0009-0006-9601-4408)
- Lu Liu (ORCID: https://orcid.org/0000-0002-6233-0705)
- Sarah Jäkel (ORCID: https://orcid.org/0000-0002-9634-2472)
- Charlene-Annett Hurler
- Niklas Junker (ORCID: https://orcid.org/0009-0006-9482-9048)
- Alan-Charles Dean (ORCID: https://orcid.org/0000-0001-8198-6737)
Institutions
- University Hospital Bonn (DE)
- Leiden University Medical Center (NL)
- German Center for Neurodegenerative Diseases (DE)
- MRC Centre for Regenerative Medicine (GB)
- Munich Cluster for Systems Neurology (DE)
- Universitätsmedizin Göttingen (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-10-26
- DOI
- https://doi.org/10.1038/s41593-026-02489-5
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00